The present invention relates to new uses for xcex1-fodrin and xcex1-fodrin fragment proteins.
Sjxc3x6gren""s syndrome is said to be an autoimmune disease whose cardinal manifestation is a sicca syndrome associated with keratoconjunctivitis sicca and chronic sialadenitis but the mechanisms of its onset remain to be elucidated.
Diagnosed as Sjxc3x6gren""s syndrome is either a glandular (primary) syndrome which is confined to the lacrimal and salivary glands and clinically characterized by the so-called dry eye/dry mouth symptom or an extraglandular (secondary) syndrome characterized by a broad spectrum of generalized symptoms involving the liver, lung, thyroid gland, pancreas, kidney, and other organs. It is also known that the glandular syndrome progresses to the extraglandular syndrome in many cases and, though rarely, gives rise to malignant lymphoma.
As autoantibodies detected in Sjxc3x6gren""s syndrome, SS-A/Ro and SS-B/La are known. The corresponding antigens of these antibodies have already been identified but their specificity is low, with patients possessing autoantibodies to these antigens accounting for 40-60% of the total population of patients with Sjxc3x6gren""s syndrome. Moreover, in many cases SS-A/Ro- or SS-B/La-positive patients have complications such as systemic lupus erythematosus and rheumatism [Journal of Clinical Investigation, 87, p68-76, 1991; and Nucleic Acids Research, 17, p2233-2244, 1989].
In view of the above findings, those antibodies or antigens are regarded as indicators of all autoimmune diseases inclusive of Sjxc3x6gren""s syndrome. However, neither a specific autoantigen nor a specific autoantibody that could be a specific indicator of primary Sjxc3x6gren""s syndrome is not heretofore known.
xcex1-Fodrin is one of subunits of fodrin which is a macromolecular actin-binding protein present immediately beneath the plasma membrane of cells. Fodrin forms high-order structures such as the fodrin network and is considered to be associated with the morphogenesis of cells and the migration of secretory granules to the surface membrane.
It has recently been reported that in programmed cell deaths such as apoptosis, the full-length xcex1-fodrin of 240K is restrictively cleaved by proteases to yield xcex1-fodrin protein fragments [Journal of Biological Chemistry, 270, p6425-6428, 1995]. Moreover, as the proteases causing such restricted cleavage of xcex1-fodrin, trypsin, chymotrypsin, and calpain are known [Journal of Neuroscience, 8, p.2640-2651, 1988].
However, the relationship of this restricted cleavage of xcex1-fodrin to Sjxc3x6gren""s syndrome remains to be known.
Therefore, if an autoantibody or autoantigen specific to Sjxc3x6gren""s syndrome, particularly primary Sjxc3x6gren""s syndrome, is discovered, not only will the diagnosis of Sjxc3x6gren""s syndrome be facilitated and made more definite but the prophylaxis and therapy of Sjxc3x6gren""s syndrome, particularly primary Sjxc3x6gren""s syndrome, and, hence, prevention of progression of primary to secondary syndrome will be made possible by establishing a tolerance to autoantigens prior to onset of the disease or after the onset.
Furthermore, detailed analyses for elucidation of the mechanisms of onset of Sjxc3x6gren""s syndrome will also become feasible.
In view of the above state of the art, the inventors of the present invention did much research and not only discovered autoantibodies which are specifically detected in primary Sjxc3x6gren""s syndrome but also found that the corresponding autoantigens are xcex1-fodrin and xcex1-fodrin fragment proteins.
The inventors further found that Sjxc3x6gren""s syndrome can be prevented and cured by administering such an autoantigen.
The present invention, therefore, is directed to:
(1) A pharmaceutical composition comprising xcex1-fodrin, a mutein thereof, a fragment thereof, or a salt thereof with a pharmaceutically acceptable carrier,
(2) A composition for preventing or treating autoimmune disease comprising xcex1-fodrin, a mutein thereof, a fragment thereof, or a salt thereof with a pharmaceutically acceptable carrier,
(3) A composition for preventing or treating Sjxc3x6gren""s syndrome comprising xcex1-fodrin, a mutein thereof, a fragment thereof, or a salt thereof with a pharmaceutically acceptable carrier,
(4) The composition described in the above item (3) wherein the molecular weight of said xcex1-fodrin, a mutein thereof, or a fragment thereof is from about 2K to about 240K,
(5) The composition described in the above item (3) wherein said xcex1-fodrin, a mutein thereof, or a fragment thereof contains or comprises an amino acid sequence substantially shown by Arg-Gln-Lys-Leu-Glu-Asp-Ser-Tyr-Arg-Phe-Gln-Phe-Phe-Gln-Arg-Asp-Ala-Glu-Glu-Leu, (SEQ ID NO: 1)
(6) The composition described in the above item (5) wherein the molecular weight of said xcex1-fodrin, a mutein thereof, or a fragment thereof is from about 100K to about 140K,
(7) The composition described in the above item (3) wherein said xcex1-fodrin fragment is an xcex1-fodrin fragment protein available upon proteolysis of xcex1-fodrin with a protease,
(8) A diagnostic agent for autoimmune disease comprising xcex1-fodrin, a mutein thereof, a fragment thereof, or a salt thereof,
(9) A diagnostic agent for Sjxc3x6gren""s syndrome comprising xcex1-fodrin, a mutein thereof, a fragment thereof, or a salt thereof,
(10) The diagnostic agent for Sjxc3x6gren""s syndrome described in the above item (9) wherein the molecular weight of xcex1-fodrin, a mutein thereof, or a fragment thereof is from about 2K to about 240K,
(11) The diagnostic agent for Sjxc3x6gren""s syndrome described in the above item (9) wherein said xcex1-fodrin, a mutein thereof, or a fragment thereof contains or comprises an amino acid sequence substantially shown by Arg-Gln-Lys-Leu-Glu-Asp-Ser-Tyr-Arg-Phe-Gln-Phe-Phe-Gln-Arg-Asp-Ala-Glu-Glu-Leu, ( SEQ ID NO:1)
(12) The diagnostic agent for Sjxc3x6gren""s syndrome described in the above item (11) wherein the molecular weight of xcex1-fodrin, a mutein thereof, or a fragment thereof is from about 100K to about 140K,
(13) A method for detection or assay of an antibody against xcex1-fodrin, a mutein thereof, a fragment thereof, or a salt thereof, which comprises contacting xcex1-fodrin, a mutein thereof, a fragment thereof, or a salt thereof with said antibody.
(14) A method for preventing or treating autoimmune disease which comprises administering to a patient a therapeutically effective amount of xcex1-fodrin, a mutein thereof, a fragment thereof, or a salt thereof with a pharmaceutically acceptable carrier,
(15) The method described in the above item (14), wherein autoimmune disease is Sjxc3x6gren""s syndrome,
(16) A method for diagnosing autoimmune disease which comprises detecting or assaying autoantibody against xcex1-fodrin, a mutein thereof, a fragment thereof, or a salt thereof, which comprises contacting xcex1-fodrin, a mutein thereof, a fragment thereof, or a salt thereof with said autoantibody,
(17) The method described in the above item (16), wherein autoimmune disease is Sjxc3x6gren""s syndrome,
(18) Use of xcex1-fodrin, a mutein thereof, a fragment thereof, or a salt thereof for the manufacture of a medicament for preventing or treating autoimmune disease,
(19) Use of xcex1-fodrin, a mutein thereof, a fragment thereof, or a salt thereof for the manufacture of a medicament for preventing or treating Sjxc3x6gren""s syndrome,
(20) Use of xcex1-fodrin, a mutein thereof, a fragment thereof, or a salt thereof for the manufacture of a medicament for diagnosing autoimmune disease, or
(21) Use of xcex1-fodrin, a mutein thereof, a fragment thereof, or a salt thereof for the manufacture of a medicament for diagnosing Sjxc3x6gren""s syndrome.